Acute Myeloid Leukemia Coverage From Every Angle

Venetoclax (Venclexta®)

Posted: Monday, March 2, 2020

Acute myeloid leukemia (AML) commonly affects the elderly, with a median age of 67 years at diagnosis.1,2 Elderly patients (≥ 65 years) with AML often respond poorly to induction chemotherapy and demonstrate increased resistance to treatment, perhaps as a result of a higher frequency of adverse genomic features.1 Furthermore, because of comorbidities, compromised organ function, and poor performance status, many older patients may not be candidates for conventional cytotoxic induction therapies. Thus, the need for better lower-intensity therapeutic approaches in this patient population is clear.

Clinical Development of Venetoclax in AML

In November 2018, the U.S. Food and Drug Administration granted accelerated approval for the BCL2 inhibitor venetoclax in combination with azacitidine or decitabine or low-dose cytarabine in the treatment of patients aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy.3 According to many experts, including Rebecca Olin, MD, MS, Medical Director of the Inpatient Hematology/BMT Unit at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, venetoclax may be considered “the most practice-changing drug [in AML] over the past few years.” Compared with the previous standard of care for these patients, Dr. Olin continued, which was a hypomethylating agent alone, the combination of a hypomethylating agent plus venetoclax “results in significantly better response rates, with a shorter time to response, and a good duration of response, including some minimal residual disease–negative responses. These excellent response rates were seen across a variety of clinical and molecular subsets of AML. Venetoclax plus a hypomethylating agent or low-dose cytarabine is currently listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML4 as a preferred treatment option for older patients who are not candidates for or decline intensive induction treatment strategies.” Venetoclax has also been approved for the treatment of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (see https://jnccn360.org/cll/jnccn-spotlights/venetoclax/).

Venetoclax may be considered the most practice-changing drug in AML over the past few years.

The approval of venetoclax in AML was based on two open-label nonrandomized trials. Study M14-358 (ClinicalTrials.gov identifier NCT02203773) assessed venetoclax in combination with azacitidine (n = 67) or decitabine (n = 13) in newly diagnosed patients with AML.5,6 Study M14-387 (NCT02287233) evaluated venetoclax in combination with low-dose cytarabine (n = 61) in newly diagnosed patients with AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder.7

A follow-up study attempted to determine the optimal dose of venetoclax-based therapy in elderly patients with newly diagnosed AML.8 The investigators supported the use of venetoclax at 400 mg daily in combination with a hypomethylating agent and 600 mg daily in combination with low-dose cytarabine (ie, the next highest dose evaluated less than 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

Mechanism of Action and Clinical Implications

Speculating about the mechanism of action of venetoclax, Jones et al observed that leukemic stem cells in de novo AML rely on amino acid metabolism for oxidative phosphorylation and survival.9 With that in mind, they determined that the combination of venetoclax with azacitidine was able to induce leukemic stem cell toxicity in vitro by decreasing amino acid uptake, as confirmed by decreased α-ketoglutarate and increased succinate levels, suggestive of inhibition of electron transport chain complex II. This process was observed in a clinical trial of leukemic stem cells derived from patients with AML treated with this combination.10

Given the unique mechanism of action of venetoclax, it is not surprising that this therapy presents some practical challenges, including but not limited to the rapidity of responses, the rate and depth of cytopenias, and issues related to drug-drug interactions.11,12 A clinical protocol for initiating venetoclax was proposed by Jonas and Pollyea.11 They first identify patients who do not have rapidly progressive disease and quickly start the process for obtaining venetoclax. They carefully monitor patients in the outpatient setting two to three times a week via blood cell counts and transfusions according to clinical needs or institutional thresholds.11 Most patients receive their first month’s supply of venetoclax within 7 to 14 days of the initial request.

When Treatment Is Too Rapidly Effective: Tumor-Lysis Syndrome

Clinicians need to be aware that tumor-lysis syndrome is a complication associated with highly effective treatment of certain malignancies, including AML. It is caused by the release of leukemia cell contents resulting in electrolyte and metabolic abnormalities that may lead to catastrophic clinical sequelae.13 Venetoclax poses a risk for tumor-lysis syndrome, particularly in patients with CLL, who require a stepwise ramp up.

“Although also observed in AML,” Dr. Olin explained, “tumor lysis has been largely biochemical.” Changes in blood chemistries consistent with tumor-lysis syndrome that require prompt management can occur as early as 6 to 8 hours after the first dose of venetoclax and at each dose increase, so monitoring of serum electrolytes is required.14

The potential to eliminate leukemic stem cells is supported by the fact that among patients with AML not eligible for intensive chemotherapy who were treated with venetoclax in combination with azacitidine or decitabine, 45% of those achieving complete remission also experienced measurable residual disease eradication, with fewer than 10−3 leukemic cells observed in bone marrow samples at the time of response assessment.14

Venetoclax Administration

For tumor lysis prophylaxis, all patients should receive allopurinol and intravenous or oral hydration. “If the white blood cell count is high at diagnosis,” Dr. Olin advised, “patients can receive hydroxyurea to lower it to < 25 × 109/L before treatment is started.”

For tumor lysis prophylaxis, all patients should receive allopurinol and intravenous or oral hydration.

“Generally, this regimen—the hypomethylating agent plus venetoclax—is administered in the outpatient setting. The hypomethylating agent [azacitidine, decitabine] or low-dose cytarabine is given either intravenously or subcutaneously on the same day that venetoclax is started,” Dr. Olin said. Although a ramp-up period of 5 days is described in the prescribing information for venetoclax,15 “many centers, including ours, do not use a ramp-up,” Dr. Olin continued. If patients are hospitalized when they are diagnosed and treatment started quickly, it also can be initiated for inpatients, as needed.

Supporting Patients and Families

“This can be a very scary time for patients,” Stephany L. Rodriguez, RN, MS, NP, also of UCSF, told JNCCN 360. “The support of a knowledgeable care team can make all the difference,” she said.

It is often the nurses and advanced practice providers who educate patients, families, and caregivers about the symptoms of tumor lysis, Ms. Rodriguez noted. “For example, patients should be encouraged to maintain adequate fluid intake and to accurately monitor fluid input and output while receiving venetoclax.” This is also a good opportunity, Ms. Rodriguez added, “to educate patients on the importance of good adherence with both venetoclax and supportive care medications,” such as antimicrobials and/or antiemetics. Newly diagnosed patients, she pointed out, often need education and coaching about how to make effective use of antiemetic medication.

“As with any new treatment regimen, patients and family members need to know how to contact their care team,” Ms. Rodriguez noted. “They also need to be clear about when to call, such as for severe nausea, vomiting, diarrhea, constipation, inability to maintain adequate fluid intake, or neutropenic fever.”

Response to Venetoclax-Based Regimen

Rapid responses have come to be expected in previously untreated patients with AML, and this is considered a strength of venetoclax-based therapies. The median time to complete response with single-agent hypomethylating agents was 4 cycles with azacitidine and 4.5 cycles with decitabine.16 In contrast, the median time to complete response/complete response with incomplete blood cell count recovery with the combination of venetoclax and azacitidine or decitabine was 1.2 months and 1 month, respectively.1,5,7

Commenting on the clinical implications of these findings, Dr. Olin told JNCCN 360: “This fast response, in combination with the myelosuppression associated with venetoclax-based therapy, means that response assessment by bone marrow biopsy should occur after one to two cycles of therapy, versus the four to six cycles that was the standard when using azacitidine or decitabine alone.”

Venetoclax-Associated Toxicities

The overall toxicity profile of venetoclax with hypomethylating agents or low-dose cytarabine includes hematologic toxicities, with cytopenias occurring in about 40% of patients and grade 3 or higher infectious complications, in 33% of patients.5

According to Dr. Olin, dose adjustment and/or delay of subsequent treatment cycles (ie, holding both venetoclax and hypomethylating agent/cytarabine) may be necessary in patients experiencing hematologic toxicities, particularly in those with ongoing cytopenias whose restaging marrow assessment shows less than 5% to 10% blasts. Despite these toxicities, just 3% of patients experienced early death, reinforcing the safety of this regimen in this setting.1

In the setting of continued neutropenia, administration of granulocyte-colony stimulating factor and a 50% dose reduction for the associated hypomethylating agent may also be considered,12 although the long-term outcomes of these modifications are not known. Additionally, the possibility that delayed hematologic recovery may be due to relapse of disease, rather than toxicity, must be considered prior to dose modification.

Because of the degree of myelosuppression associated with this regimen, Dr. Olin advised that all patients should receive antibiotic prophylaxis such as a quinolone or third-generation cephalosporin and noted that “many practitioners also prescribe an antifungal, such as voriconazole or posaconazole.” She pointed out, however, that “the venetoclax dose needs to be adjusted when concurrent antifungal prophylaxis is used in this scenario.”

Other adverse events associated with venetoclax-based therapy included nausea, vomiting, diarrhea, constipation, fatigue, neutropenia/febrile neutropenia, thrombocytopenia, and anemia.12

Ongoing Trials

Venetoclax is currently being studied in clinical trials of patients with refractory AML as well as in B-cell lymphomas. A dose-escalation study, for example, is underway; it is evaluating the safety, tolerability, pharmacokinetics, and efficacy of venetoclax in combination with the targeted agent gilteritinib in patients with relapsed or refractory FLT3-positive AML whose disease has failed to respond to and/or who have relapsed or experienced disease progression after at least one prior therapy (NCT03625505).

Venetoclax plus a hypomethylating agent or low-dose cytarabine is the new standard of care.

In summary, “because of its significantly better effectiveness versus hypomethylating agents alone, venetoclax plus a hypomethylating agent or low-dose cytarabine is the new standard of care against which other therapies in development must be compared,” Dr. Olin reiterated. Certain key toxicities must be managed, particularly cytopenias. Response assessment should occur earlier with subsequent dose or schedule adjustment. “For patients with AML who are unfit or even borderline unfit for induction, this treatment approach may offer the opportunity for remission with good quality of life, and even consideration of the curative option of reduced intensity allogeneic transplant,” Dr. Olin concluded.

 

Disclosures

Rebecca Olin, MD, MS, has received clinical research support from or served on data safety monitoring board for Astellas Pharma US, Inc., Daiichi-Sankyo Co., Genetech, Inc., and Pfizer Inc. She also has served on a scientific advisory board or as a consultant or expert witness for Amgen Inc., Genentech, Inc., and Jazz Pharmaceuticals Inc.

Dr. Olin’s spouse has served as site principal investigator for MedImmune, Spectrum, and Mirati and has also received research funding from Novartis and AstraZeneca.

Stephany L. Rodriguez, RN, MS, NP, reported no conflicts of interest. 

 

References

  1. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019;133:7–17.
  2. National Cancer Institute. SEER cancer statistics review, 1975-2016. 2018. Available at: https://seer.cancer.gov/csr/1975_2016/. Accessed February 26, 2020.
  3. FDA approves venetoclax in combination for AML in adults. Available at https://www.fda.gov/drugs/fda-approves-venetoclax-combination-aml-adults. Accessed January 25, 2020.
  4. Tallman MS, Altman JK, Appelbaum FR, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Acute Myeloid Leukemia. Version 3.2020—December 23, 2019. Accessed February 11, 2020. To view the most recent version of these guidelines, visit NCCN.org.
  5. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018;19:216–228.
  6. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019;133:7–17.
  7. Wei AH, Strickland Jr SA, Hou J-Z, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol 2019;37:1277–1284.
  8. Agarwal S, Gopalakrishnan S, Mensing S, et al. Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: an exposure-response analysis. Hematol Oncol 2019;37:464–473.
  9. Jones CL, Stevens BM, D’Alessandro A, et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell 2018;34:724–740.
  10. Pollyea DA, Stevens BM, Jones CL, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med 2018;24:1859–1866.
  11. Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia 2019;33:2795–2804.
  12. Knight T, Edwards H, Taub JW, et al. Evaluating venetoclax and its potential in treatment-naive acute myeloid leukemia. Cancer Manag Res 2019;11:3197–3213.
  13. Howard SC, Jones DP, Pui C-H. The tumor lysis syndrome. N Engl J Med 2011;364:1844–1854.
  14. Pollyea DA, Pratz KW, Jonas BA, et al. Venetoclax in combination with hypomethylating agents induces rapid, deep, and durable responses in patients with AML ineligible for intensive therapy. Blood 2018;132(Suppl 1):285.
  15. Venclexta (venetoclax). FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208573s011s014s015lbl.pdf. Accessed February 11, 2020.
  16. Pleyer L, Stauder R, Burgstaller S, et al. Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry of the AGMT-Study Group. J Hematol Oncol 2013;6:32.



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